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Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes

Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes
Literature review current through: Sep 2023.
This topic last updated: Jul 14, 2022.

INTRODUCTION — Allogeneic hematopoietic cell transplantation (HCT, also called hematopoietic stem cell transplantation) is the treatment of choice for many hematologic disorders. Allogeneic HCT involves use of hematopoietic progenitor cells from a relative or unrelated person following a preparative regimen. Pulmonary complications are a common cause of morbidity and occasionally mortality following this procedure [1-4].

The pulmonary complications of allogeneic HCT will be reviewed here. The determination of eligibility for HCT, infectious complications of HCT, supportive care following HCT, and pulmonary complications of autologous HCT are discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation" and "Overview of infections following hematopoietic cell transplantation" and "Early complications of hematopoietic cell transplantation" and "Pulmonary complications after autologous hematopoietic cell transplantation".)

OVERVIEW AND DEFINITIONS — Hematopoietic cell transplantation (HCT) is a general term for a variety of procedures in which the patient is treated with chemotherapy and/or irradiation (ie, the "preparative regimen") followed by the infusion of hematopoietic progenitor cells. Progenitor cells can come from a variety of sources (eg, bone marrow, peripheral blood, cord blood). (See "Sources of hematopoietic stem cells".)

Allogeneic versus autologous HCT — Allogeneic HCT refers to the use of hematopoietic progenitor cells collected from a relative (which can be human leukocyte antigen [HLA] identical, haploidentical, or mismatched) or an unrelated donor (volunteer or umbilical cord donor). Autologous HCT refers to collection of hematopoietic progenitor cells from the patient prior to the administration of high dose chemotherapy designed to target an underlying malignancy, followed by reinfusion of these cells.

Many of the pulmonary complications of allogeneic HCT also occur with autologous HCT, but there are some important differences. Prevention of graft rejection and graft-versus-host disease (GVHD) in allogeneic HCT necessitates more intense immunosuppression than that required for autologous HCT, which does not have these complications. Allogeneic grafts may be associated with development of potentially detrimental GVHD. On the other hand, some allogeneic HCT patients may benefit from a graft-versus-tumor effect. (See "Biology of the graft-versus-tumor effect following hematopoietic cell transplantation".)

Autologous HCT is discussed separately. (See "Multiple myeloma: Use of hematopoietic cell transplantation" and "Pulmonary complications after autologous hematopoietic cell transplantation" and "Determining eligibility for autologous hematopoietic cell transplantation".)

Preparative conditioning regimen — Preparative conditioning regimens are designed to ablate or suppress the host bone marrow and thereby prevent graft rejection, but have the potential to cause pulmonary toxicity. Preparative regimens for HCT have been termed myeloablative (eg, total body irradiation ≥5 Gy, high dose busulfan), nonmyeloablative (fludarabine, cyclophosphamide, antithymocyte globulin, irradiation ≤2 Gy), and reduced intensity (eg, low dose busulfan, melphalan). The various preparative conditioning regimens are discussed in greater detail separately. (See "Preparative regimens for hematopoietic cell transplantation".)

Engraftment — The infused hematopoietic stem cells find their way to the bone marrow, where they re-establish normal production of blood cells, called engraftment. By definition, engraftment after HCT has occurred when the recipient has a peripheral blood absolute neutrophil count (ANC) of 1000/microL, or three consecutive days with a count greater than 500. Time to engraftment is variable and dependent on multiple variables, including cell source, graft composition, and type of conditioning, but on average is approximately 30 days from transplant. The types of pulmonary complications that occur following allogeneic HCT vary based on the time since the transplant occurred, although some complications can occur both early and late (table 1 and table 2). (See 'Pre-engraftment period' below and 'Post hematopoietic cell engraftment' below.)

At the time of engraftment of donor hematopoietic cells, patients may develop a cytokine-driven engraftment syndrome. (See 'Engraftment syndrome' below.)

Maintenance immunosuppression — After allogeneic HCT, maintenance immunosuppression is administered to prevent graft rejection and GVHD. A commonly used regimen is the combination of methotrexate and a calcineurin inhibitor such as cyclosporine or tacrolimus; alternative or additional agents include glucocorticoids, sirolimus, mycophenolate mofetil, and also agents targeting T cell depletion. These agents contribute to the risk of pulmonary toxicity and opportunistic infections. (See "Prevention of graft-versus-host disease".)

Graft-versus-host disease — GVHD occurs when immune cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. Hyperacute GVHD, which is rare with current HLA typing, occurs in the first 14 days post HCT, acute GVHD in the first 100 days, and chronic GVHD after the first 100 days, although the specific timing is approximate. Despite preconditioning and maintenance immunosuppression to prevent GVHD, approximately 20 to 40 percent of allogeneic HCT recipients are affected by GVHD. GVHD in turn may increase the risk of certain pulmonary complications, such as the idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, bronchiolitis obliterans, and late-occurring infections. (See "Pathogenesis of graft-versus-host disease (GVHD)".)

PRE-ENGRAFTMENT PERIOD — In the pre-engraftment period from HCT up to engraftment (eg, about 0 to 30 days post HCT), the differential diagnosis of pulmonary complications includes infection, pulmonary edema due to cardiac and noncardiac causes such as sepsis syndrome or aspiration, diffuse alveolar hemorrhage, and engraftment syndrome (table 1).

Pulmonary infections — Infections due to aerobic gram positive and gram negative bacteria, fungi, and certain viruses occur in up to 10 percent of HCT recipients in the pre-engraftment phase and are a major contributor to mortality (figure 1) [5-7]. Among 427 consecutive allogeneic recipients, bacterial pneumonia developed in the first post-HCT month in 4 percent; fungal pneumonia in 9 percent, and viral pneumonia in 2 percent; 4 percent had suspected pneumonia without a specific organism being identified [6]. In addition to the effects of neutropenia, mucositis from the conditioning regimen contributes to the risk of infection via swallowing difficulties, aspiration, and possibly impaired mucociliary clearance [8-10]. Distinguishing clinical, radiographic, and other diagnostic features of these infections are shown in the table (table 1). A discussion of pulmonary infections that complicate HCT is provided separately. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia'.)

Bacterial pneumonia – The most common causes of bacterial pneumonia after allogeneic HCT are Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pneumoniae.

Respiratory virus infections – HCT recipients are at risk for serious lung infection due to respiratory virus infections, such as influenza A and B, parainfluenza viruses (PIV) especially PIV 3, respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; the virus that causes coronavirus disease 2019 [COVID-19]). Lymphopenia appears to be an important risk factor for respiratory virus infection. (See "COVID-19: Considerations in patients with cancer".)

Fungal pneumoniaAspergillus pneumonia is the most common fungal pneumonia among HCT recipients who have been given antifungal prophylaxis [6]. In neutropenic patients, Aspergillus pneumonia may present with the classic triad of fever, pleuritic chest pain, and hemoptysis, although this triad is frequently not present. The radiographic appearance is varied and includes single or multiple nodules with or without cavitation, patchy or segmental consolidation, or peribronchial opacities (image 1). A characteristic feature of Aspergillus nodules in the neutropenic patient is a surrounding ground glass opacity (the halo sign) that reflects angioinvasion and hemorrhage into the surrounding tissue (image 2). However, the halo sign is not specific to Aspergillus and can be seen with other fungi, such as Fusarium spp, agents of Mucormycosis, Candida, and Scedosporium spp.

Candida pneumonitis is rare due to the frequent use of prophylaxis with antifungal azole derivatives. In a case series of Candida pneumonitis in HCT recipients, the typical presentation was fever unresponsive to broad-spectrum antibiotics [11]. CT findings included multiple nodules ranging from 3 to 30 mm in diameter in 15 patients [11]. Air-space consolidation was present in 11 patients and in five, nodules were surrounded by discrete areas of ground-glass opacity (CT halo sign). In those patients with acute lung injury due to Candida pneumonitis, the CT scan showed extensive ground glass opacities in addition to a focal area of consolidation. The bronchoalveolar lavage grew Candida in all patients.

Pneumocystis pneumonia (PCP) is uncommon (<1 percent) in HCT recipients receiving prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX), but should be considered in patients who are not on prophylaxis or are receiving suboptimal prophylaxis, particularly in the setting of prolonged glucocorticoid therapy. (See "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia' and "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia'.)

Other unusual infections – Disseminated infection with strongyloidiasis or toxoplasmosis can present with lung involvement. (See "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia'.)

Pulmonary edema — Pulmonary edema of cardiogenic or noncardiogenic origin can occur in the first month after HCT, sometimes complicating other processes such as pneumonia, sepsis, the engraftment syndrome, or hyperacute GVHD. (See 'Engraftment syndrome' below and 'Hyperacute and acute graft-versus-host disease' below.)

Cardiac dysfunction can result from previous therapy for the primary disease with cyclophosphamide, anthracyclines, or external beam chest irradiation. Arrhythmias such as atrial fibrillation are also common following transplantation. Among patients with mild cardiac dysfunction, the administration of large volumes of intravenous fluids because of mucositis or antibiotic treatment for neutropenic fever can lead to pulmonary edema. The radiographic manifestations of cardiogenic pulmonary edema include interlobular septal thickening, cephalad vascular distribution, ground glass opacification (sometimes in a perihilar "butterfly" distribution) (image 3), pleural effusions, and sometimes cardiomegaly. The plasma brain natriuretic peptide (BNP) is usually elevated and the echocardiogram shows left ventricular dysfunction. The evaluation of cardiogenic pulmonary edema is discussed separately. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)

On the other hand, noncardiogenic pulmonary edema can be induced by sepsis, aspiration pneumonia, viral infection (eg, influenza) [12], toxic effects of the conditioning regimen, or hyperacute GVHD. The evaluation of noncardiogenic pulmonary edema is discussed separately. (See "Noncardiogenic pulmonary edema" and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Timing and organ involvement'.)

Patients with severe hepatic veno-occlusive disease (another complication of HCT) can present with either cardiogenic or noncardiogenic pulmonary edema with pleural effusions. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Clinical presentation'.)

Engraftment syndrome — The engraftment syndrome is a noninfectious complication of HCT that is reported in 13 to 20 percent of allogeneic HCT recipients [13-16]. It develops at a median of 10 days (range 9 to 12) following HCT during the time of neutrophil recovery [15].

Pathogenesis – In terms of pathogenesis, the pulmonary manifestations of the engraftment syndrome are thought to be due to a proinflammatory state [17,18] with diffuse alveolar damage and consequent capillary leakage. The presence of a skin rash raises the possibility that the engraftment syndrome is a manifestation of hyperacute GVHD, which is extremely rare with current HLA typing methodologies. However, the exact findings on skin biopsy in patients with engraftment syndrome include mild edematous changes of the epidermal-dermal junction, absence of lymphocytic infiltration, presence of neutrophils in the lumen of small venules and capillaries [14]. These findings are rather non-specific and skin biopsy is not recommended. In contrast, skin biopsy in acute GVHD typically shows interface dermatitis (vacuolization of the basal layer of the epidermis and a lymphocytic infiltrate in the superficial dermis) and epidermal apoptotic keratinocytes. However, the accuracy of differentiation of these processes by skin biopsy is unclear and patients who experience engraftment syndrome are more likely to develop subsequent acute GVHD [15]. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Skin biopsy'.)

Clinical features – Symptoms associated with engraftment syndrome are typically mild and most commonly include fever and rash (diffuse erythematous), with variable presence of dyspnea, weight gain, diarrhea, and altered mental status.

Findings on chest computed tomography include bilateral ground-glass opacification, hilar or peribronchial consolidation, and thickening of interlobular septa [19-21]. Pleural effusions were common in one series [22,23]. Bronchoalveolar lavage findings are nonspecific, but do not show evidence of infection. In two patients who underwent lung biopsy, diffuse alveolar damage was noted.

Diagnosis – The diagnosis of engraftment syndrome requires fulfillment of three major criteria or two major and one or more minor criteria [24]. The three major diagnostic criteria are noninfectious fever ≥38.3˚C, an erythematous maculopapular rash (not attributable to a drug or acute GVHD), and diffuse pulmonary opacities consistent with noncardiogenic pulmonary edema [13,14,20,25-29]. Minor criteria include liver dysfunction (total bilirubin >2 mg/dL or transaminase levels >2 times normal), kidney insufficiency (serum creatinine >2 times baseline), and transient encephalopathy not explainable by other causes.

The evaluation and management of the engraftment syndrome are discussed separately. (See "Pulmonary complications after autologous hematopoietic cell transplantation", section on 'Engraftment syndrome and PERDS'.)

Hyperacute and acute graft-versus-host disease — Hyperacute and acute GVHD are the consequence of HLA mismatch between the donor and recipient. With accurate HLA typing using molecular methods, hyperacute GVHD is very rare.

Hyperacute GVHD occurs in the first 14 days post-transplant and is frequently (88 percent) associated with both skin involvement and noncardiogenic pulmonary edema. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Clinical and histological manifestations'.)

Acute GVHD develops in the first 100 days following allogeneic HCT, although it is recognized that signs and symptoms can occur later in some patients' acute GVHD. It rarely affects the lung directly, although it can be a risk factor for noncardiogenic pulmonary edema, diffuse alveolar hemorrhage, and later development of airflow obstruction. (See 'Diffuse alveolar hemorrhage' below and 'Pulmonary edema' above and 'Airflow obstruction and bronchiolitis obliterans' below and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

POST HEMATOPOIETIC CELL ENGRAFTMENT — The spectrum of pulmonary complications changes from pre-engraftment to post-engraftment (>30 days after HCT, approximately). Infections continue to be a significant cause of morbidity and mortality, although the specific organisms differ (figure 1). The idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, and pulmonary alveolar proteinosis are infrequent, but can cause substantial pulmonary morbidity (table 2).

Noncardiogenic and cardiogenic pulmonary edema are more common pre-engraftment, but also occur post-engraftment. Pulmonary thromboembolism has not specifically been associated with allogeneic HCT, but is a potential complication of hospitalization and severe medical illness.

Pulmonary infections — In the post-engraftment period (ie, three weeks to three months), impaired cellular and humoral immunity are the main factors contributing to pulmonary infection. In the late post-engraftment period (ie, more than three months after HCT), infectious complications are less common; the major risk factors for infection in this phase are chronic graft-versus-host disease (GVHD) and its therapy. The organisms that cause lung infection in the post-engraftment period are shown in the figure (figure 1) [30] and are discussed in detail separately. (See "Overview of infections following hematopoietic cell transplantation".)

The features related to post-engraftment pulmonary infection are reviewed here:

Bacteria – Lung infection due to S. pneumoniae and H. influenzae, although less frequently than in the pre-engraftment phase, continues to occur in the first year post-HCT. During this period, numerous other bacteria can cause infection, including Legionella, Nocardia, and Actinomyces. (See "Overview of infections following hematopoietic cell transplantation".)

Mycobacteria – Mycobacterial and atypical mycobacterial infections are occasionally reported after HCT [31]. The overall incidence of M. tuberculosis infections in allogeneic bone marrow transplant patients is 1 to 3 percent [32]. Total body irradiation and chronic GVHD (requiring enhanced immunosuppressive therapy) are associated with an increased risk of tuberculosis. Allogeneic HCT is associated with depressed delayed-type hypersensitivity reactions, so skin testing with purified protein derivative (PPD) is not likely to be helpful. Sputum samples are usually diagnostic. (See "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia'.)

M. haemophilum and M. avium complex can be important pulmonary pathogens after HCT [31-34]. The diagnosis of M. haemophilum should be suspected in patients who have skin nodules or joint inflammation with or without pulmonary opacities. Confirmation of the diagnosis requires special culture conditions for isolation; thus, close communication with the microbiology laboratory is essential. Failure to recognize this treatable pathogen in a timely fashion can lead to a fatal outcome.

The evaluation and of mycobacterial infections are discussed separately. (See "Diagnosis of pulmonary tuberculosis in adults" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of Mycobacterium avium complex pulmonary infection in adults".)

Cytomegalovirus – Cytomegalovirus (CMV) pneumonitis rarely occurs during the pre-engraftment period as the major risk involves cellular immunity. However, once engraftment occurs, it should be included in the differential diagnosis of cough, fever, or dyspnea, even in the absence of radiographic abnormalities. The risk is highest in seropositive recipients who receive marrow from a seronegative donor. Pre-emptive and prophylactic antiviral therapy has markedly reduced the incidence and severity of CMV disease and delayed its onset, although CMV must be considered in any allogeneic HCT recipient who is CMV seropositive or received hematopoietic cells from a seropositive donor [35]. Chest radiographs typically show patchy areas of ground glass or consolidation (image 4). High resolution computed tomography (HRCT) may show ground glass attenuation, parenchymal opacification, or innumerable small (<5 mm) nodules [36,37].

CMV pneumonitis is discussed separately. (See "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia' and "Overview of diagnostic tests for cytomegalovirus infection".)

Respiratory viruses – Community-acquired infections with influenza, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), parainfluenza, respiratory syncytial virus, adenoviruses, and human metapneumovirus can occur during the post-engraftment period (figure 1 and table 2). Some specific details that pertain to post-engraftment lung infection in HCT recipients are provided below. Viral infections following HCT are discussed in greater detail separately. (See "Overview of infections following hematopoietic cell transplantation" and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Other respiratory viruses' and "COVID-19: Considerations in patients with cancer".)

Influenza virus has the potential to cause serious lung infection and respiratory failure among HCT recipients [38]. This was noted in particular with the 2009 pandemic influenza A/H1N1 [39]. Infections with influenza tend to be seasonal, predominantly between November and April in North America. Progression to pneumonia is more likely among lymphopenic patients and thus is more common pre-engraftment than post-engraftment [38]. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

Parainfluenza virus, a recognized cause of both upper and lower respiratory tract disease after HCT, affects 2 to 7 percent of HCT recipients and is seasonal. There are four serotypes, with type 3 being the most common cause of lung infection after HCT; the incubation period is one to four days. Upper respiratory tract symptoms may precede lower tract disease by several days, although pneumonia may occur without upper respiratory symptoms. Parainfluenza virus is also associated with asymptomatic shedding in HCT recipients. The HRCT findings in parainfluenza virus pneumonia include small peribronchial nodular opacities, ground glass opacities, and/or air space consolidation (image 5). The evaluation and treatment of parainfluenza virus are discussed separately. (See "Parainfluenza viruses in adults", section on 'Clinical manifestations'.)

Pneumonia due to respiratory syncytial virus (RSV) affects adult patients as well as children and has a high mortality after HCT [40]. There is a marked seasonal variation in incidence, with the peak between January and March. In addition, RSV can occur as a nosocomial outbreak [41]. The presence of concomitant otitis media or sinusitis should raise the suspicion for RSV infection. Diffuse ground glass opacities are the most common radiographic pattern associated with RSV pneumonitis. The diagnosis can be established by culture or rapid immunofluorescence of respiratory secretions, throat swabs, or nasopharyngeal washes. (See "Respiratory syncytial virus infection: Clinical features and diagnosis" and "Respiratory syncytial virus infection: Treatment".)

Adenoviruses, which can be isolated in 3 to 5 percent of patients after HCT, should be considered in the differential diagnosis of pulmonary infection [42]. Affected patients present with pharyngitis, tracheitis, bronchitis, pneumonitis, enteritis, hemorrhagic cystitis, or disseminated disease and may progress to fatal pneumonia. The specific pattern of symptoms depends at least in part on the particular serotype and on the age of the recipient. Younger HCT recipients appear to be at risk for more severe infection. Asymptomatic shedding of adenovirus can often be detected in cultures from the pharynx, respiratory secretions, stool, or urine two to three months post-HCT [43]. The clinical manifestations, diagnosis, and management of adenovirus lung infection are discussed in detail separately. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Treatment'.)

Human metapneumovirus is emerging as a pathogen affecting HCT recipients and is discussed separately. (See "Human metapneumovirus infections".)

Human herpesvirus 6 – Pneumonia due to human herpesvirus-6 (HHV-6) has been reported after HCT, although active pneumonitis due to this virus appears uncommon [44,45]. HHV-6 reactivation occurs in approximately half of allogeneic HCT recipients and may account for some cases of pneumonitis previously considered to be idiopathic [46,47] (see 'Idiopathic pneumonia syndrome' below). The clinical manifestations of HHV-6 infection are poorly described, and the prevalence of HHV-6 as a cause of interstitial pneumonia post-HCT remains to be determined. The diagnosis of HHV-6 as a cause of pneumonitis has been drawn into question given that this virus is latent in lymphocytes, which complicates the interpretation of histopathology. (See "Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults", section on 'Pneumonitis' and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Other possible associations'.)

Fungal infection – During the post-engraftment period, patients are at risk for infection with aspergillosis, other invasive molds, and Pneumocystis jirovecii (formerly P. carinii) pneumonia (PCP) (table 2). The median time of onset of Aspergillus infection is 100 days post-HCT; risk factors include older age, the presence and severity of GVHD, glucocorticoid therapy, and leukopenias. The radiographic features of Aspergillus infection are described above. (See 'Pulmonary infections' above and "Overview of infections following hematopoietic cell transplantation" and "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Pulmonary aspergillosis' and "Diagnosis of invasive aspergillosis", section on 'Diagnostic modalities' and "Clinical manifestations and diagnosis of Fusarium infection", section on 'Pneumonia'.)

Pneumocystis prophylaxis has reduced the risk of Pneumocystis pneumonia, which is a rare infection in patients who receive prophylaxis and take their medications. PCP is usually associated with diffuse radiographic opacities, but can occasionally present with focal opacities, cavitations, or a normal initial chest radiograph. Rarely, the conventional chest radiograph is normal in PCP, but HRCT of the chest shows ground glass opacities. PCP is described in greater detail separately. (See "Overview of infections following hematopoietic cell transplantation" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".).

Toxoplasmosis – Reactivation of toxoplasmosis causing lung infection is rare following allogeneic HCT, particularly because most HCT candidates are tested for IgG and IgM antibodies to toxoplasmosis and, if positive, offered a course of therapy prior to HCT. The infection typically develops in the second month after transplantation in patients with a positive pretransplant serology who have not received preemptive treatment. The presence of neurologic toxoplasmosis should prompt assessment for disseminated disease. The radiographic presentation of toxoplasmosis is similar to that of Pneumocystis; Toxoplasma tachyzoites can be identified in bronchoalveolar lavage (BAL) fluid. The clinical manifestations and diagnosis of toxoplasmosis are discussed separately. (See "Toxoplasmosis in patients with HIV", section on 'Clinical presentation' and "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia' and "Diagnostic testing for toxoplasmosis infection".)

Idiopathic pneumonia syndrome — The idiopathic pneumonia syndrome (IPS) is an important complication that develops in up to 10 percent of patients and generally occurs within four months after HCT [20,48-53]. IPS may represent a heterogeneous group of disorders that result in the common pathologic findings of interstitial pneumonitis and/or diffuse alveolar damage.

Clinical criteria – A consensus conference defined IPS as a clinical syndrome that fulfills the following criteria [52,54]:

Widespread alveolar injury, defined as multilobar opacities on chest radiograph or computed tomography (CT) plus signs and symptoms of pneumonia plus evidence of abnormal pulmonary physiology manifested by an increased alveolar-arterial oxygen gradient or the need for supplemental oxygen.

Absence of lower respiratory tract infection, as determined by a negative bronchoalveolar lavage or lung biopsy, ideally followed by a second negative invasive test within two weeks. A broad array of microbiologic tests is used to exclude infection. Appropriate tests depend on the clinical features; examples are included in the table (table 2). Newer methods of quantitative polymerase chain reaction (PCR) for a broad spectrum of pathogens may identify additional potential culprits, although the etiologic importance of such agents is not entirely clear. Nonetheless, it is possible that certain viruses (eg, HHV-6) may account for some cases of pneumonitis previously considered to be idiopathic [47]. (See 'Pulmonary infections' above and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Other possible associations'.)

Absence of cardiac dysfunction, acute renal failure, or iatrogenic fluid overload as etiology for pulmonary dysfunction.

Pathogenesis – The exact pathogenesis of IPS is not known, but the intensity of the preparative conditioning regimen has been implicated as a contributing factor (see 'Preparative conditioning regimen' above and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Evaluation", section on 'Preparative conditioning regimen'). One retrospective study of 1100 patients found a lower incidence of IPS in patients treated with a nonmyeloablative versus a myeloablative regimen (2 versus 8 percent) [49]. A systematic analysis of 20 studies (1090 patients) found an association between the incidence of IPS and the use of high dose radiotherapy, high dose cyclophosphamide, and busulfan [55]. These conditioning agents are thought to cause pulmonary epithelial injury followed by recruitment and activation of pulmonary macrophages and T-lymphocytes [52,56-58].

Clinical features and criteria for diagnosis — The onset of IPS is typically within four months after HCT [53]. The clinical manifestations include dyspnea, dry cough, hypoxemia, and diffuse radiographic opacities [54,59].

When IPS is suspected based on these features, the evaluation focuses on excluding alternate diagnoses (eg, infection, hemorrhage, alveolar proteinosis, fluid overload) and is discussed separately. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Evaluation", section on 'Evaluation'.)

Treatment — The main treatment for IPS is supportive care. Empiric antibiotics are typically administered while awaiting microbiologic study results. In addition, for patients with more severe respiratory impairment, we usually give high dose glucocorticoids of 1 mg/kg or more, although benefit has not been clearly demonstrated. As an example, in a series of approximately 81 patients who developed IPS after HCT, the disease progressed rapidly and the mortality rate was approximately 75 percent within 30 days of hospital discharge despite the use of high-dose glucocorticoid therapy in the majority of patients [49]. Similar findings were noted in another study in which the mortality rate at one year was more than 70 percent [53].

The observation that certain cytokines (eg, interleukin [IL]-6, IL-8, tumor necrosis factor alpha [TNF-alpha]) are increased in the BAL fluid of patients with IPS has led to studies of the combination of systemic glucocorticoids plus a TNF-alpha inhibitor, such as etanercept or infliximab [52,60-65]. The results suggest improved short-term, but not long-term survival. Based on these data, we rarely use anti-TNF or anti-IL-6 agents.

Examples of studies evaluating anti-TNF agents include the following:

In a series of 15 patients with IPS who were treated with glucocorticoids plus etanercept (0.4 mg/kg [maximum 25 mg]) twice weekly with a maximum of eight doses, 10 patients had a complete response within 3 to 18 days and the survival rate at 28 days was 73 percent [61]. However, survival was only 20 percent at six months, a rate that persisted out to four years.

Similar results were reported for a series of 11 patients with IPS; six received high-dose glucocorticoids alone and five also received etanercept or infliximab [62]. The overall initial response rate was 81 percent; however, survival was only 30 percent at one year.

In a series of 22 patients with IPS treated with glucocorticoids and etanercept, 28 day and 2 year survivals of 88.2 percent (95% CI 61-97 percent) and 18 percent (95% CI 4-38 percent) were reported [64].

The safety and efficacy of TNF-alpha inhibitors for IPS are under investigation. Information about clinical trials for IPS is available on the NIH clinical trials web site.

Diffuse alveolar hemorrhage — Diffuse alveolar hemorrhage (DAH) occurs in less than 1 percent of HCT and is less common following allogeneic than autologous HCT (image 6 and image 7) [66]. However, among patients who undergo allogeneic HCT for an inherited metabolic storage disease, the risk of DAH is increased among those with mucopolysaccharidosis (19 percent), but not leukodystrophies [67]. Onset can be within the first 30 days or later [68]. (See "Pulmonary complications after autologous hematopoietic cell transplantation", section on 'Diffuse alveolar hemorrhage'.)

DAH following HCT is of unclear pathogenesis, but may be a consequence of factors such as infection, acute GVHD, or diffuse alveolar damage [69]. Mortality is high (>80 percent) whether DAH is associated with infection or not [66].

Patients with DAH typically have patchy or diffuse opacities with air bronchograms on HRCT. The diagnosis is typically made by BAL, which shows progressively hemorrhagic returns on sequential lavages in the same subsegment and hemosiderin-laden macrophages on cytologic analysis. However, this rather subjective definition can be confusing especially in patients with thrombocytopenia which is typical after HCT. The diagnostic evaluation of DAH is discussed in greater detail separately. (See "The diffuse alveolar hemorrhage syndromes".)

Treatment of DAH in the setting of allogeneic HCT depends on the underlying cause of DAH.

For patients with infection-associated DAH, management includes treatment of the infection and general supportive care (eg, supplemental oxygen, mechanical ventilation).

For patients with DAH in the setting of acute GVHD, treatment is aimed at the acute GVHD with supportive care (eg, supplemental oxygen, mechanical ventilation) as necessary. Empiric antibiotics are often administered simultaneously. (See "Treatment of acute graft-versus-host disease", section on 'Management' and "Prevention of graft-versus-host disease".)

For patients without evidence of infection or acute GVHD, systemic glucocorticoids are typically administered, despite the absence of formal data. In one report, four patients with DAH following allogeneic stem cell transplantation rapidly responded to glucocorticoids, although two of the patients ultimately died of multiple organ dysfunction [70]. Conversely, no significant response to glucocorticoids was noted in a small retrospective study of children who developed DAH following allogeneic stem cell transplantation [71]. Similarly, in a larger retrospective series, there was no obvious survival benefit with glucocorticoid treatment [72].

Use of recombinant human Factor VII (rFVIIa) for refractory alveolar hemorrhage has been reported [73-80]; the risks of fatal thrombotic events must be weighed if this therapy is considered. (See "Recombinant factor VIIa: Administration and adverse effects".)

Autoimmune disease — A small number of patients have developed pulmonary involvement with autoimmune disease (eg, scleroderma, polymyositis, Sjögren's disease, antineutrophil cytoplasmic antibody-positive vasculitis) following allogeneic HCT; the mean onset is late, 31 months after HCT [81]. The majority of these patients received a myeloablative conditioning regimen. A history of prior or current GVHD was common.

In a case series and literature review, the pulmonary manifestations of autoimmune disease included nonspecific interstitial pneumonia, lymphocytic pneumonia, diffuse alveolar damage, and bronchiolitis obliterans [81]. Autoantibodies, such as antinuclear antibody, anti-Scl70, antineutrophil cytoplasmic antibody (ANCA), anti-smooth muscle, and rheumatoid factor, were frequently noted. The patients described have had a poor prognosis, despite treatment with systemic glucocorticoids [81]. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Subcategories' and "Lymphoid interstitial pneumonia" and "Treatment and prognosis of nonspecific interstitial pneumonia" and "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

Organizing pneumonia — Organizing pneumonia (OP) reported following allogeneic HCT [82,83] and may be cryptogenic or related to lung irradiation, successful treatment of CMV pneumonitis, or GVHD [84-91].

CT scans from patients with OP often reveal more extensive lung disease than expected from review of the plain chest radiograph. Radiographic patterns include patchy air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening with dilation. Patchy opacities occur most frequently in the periphery of the lung and at the lung bases. Bronchoalveolar lavage may demonstrate lymphocytosis (>25 percent lymphocytes), eosinophilia (>5 percent eosinophils), and/or neutrophilia (>30 percent neutrophils) [91].

A clinical diagnosis of OP, based on compatible HRCT features and exclusion of other diagnoses (particularly infection), may be preferred to transbronchial or surgical lung biopsy due to the risk of procedural complications [91]. Treatment with systemic glucocorticoids is usually beneficial [91]. The evaluation and management of organizing pneumonia is discussed separately. (See "Cryptogenic organizing pneumonia".)

Acute fibrinous and organizing pneumonia (AFOP) is a rare complication of allogeneic HCT that is characterized histopathologically by intra-alveolar fibrin deposition and associated organizing pneumonia [92,93]. HRCT demonstrates patchy consolidative and ground glass opacities. The diagnosis is made by lung biopsy. The optimal treatment has not been determined, but successful treatment with systemic glucocorticoids and etanercept has been reported in isolated cases [92,93]. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Rare histopathologic interstitial pneumonia patterns'.)

Malignancy — The lungs can be the site of relapse of the underlying malignancy, development of a second cancer years after HCT, and secondary lymphoproliferative disease. Recurrence of the underlying malignancy in the lung is seen most commonly after allogeneic HCT for lymphoma. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Hodgkin lymphoma: Epidemiology and risk factors" and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Post-transplant lymphoproliferative disease (PTLD) developing after allogeneic HCT is thought to be a consequence of immunosuppression, which causes a deficiency in Epstein-Barr virus (EBV) specific cytotoxic T lymphocytes [94,95]. The typical appearance of PTLD on chest CT is multiple pulmonary nodules with a peripheral or basal predominance; other patterns include patchy consolidation, mediastinal and hilar lymphadenopathy, pleural or chest wall masses and pleural effusion [96]. Biopsy and histopathologic analysis are needed for diagnosis, which typically reveals EBV. While refractory to standard chemotherapy, post-HCT lymphoproliferative disease may respond to other treatment protocols, including rituximab and reduced immunosuppression [97]. The diagnosis and management of secondary lymphoproliferative disorders are discussed separately. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Pulmonary alveolar proteinosis — Pulmonary alveolar proteinosis (PAP) has been reported as a reversible cause of respiratory failure after allogeneic HCT [98-100]. PAP presents with dyspnea and perihilar opacities in a "bat-wing" distribution on chest radiograph (image 8 and image 9). The diagnosis is made by bronchoalveolar lavage (BAL); the BAL fluid has a characteristic milky appearance and stains positively for lipoproteins. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults" and "Treatment and prognosis of pulmonary alveolar proteinosis in adults" and "Mucopolysaccharidoses: Clinical features and diagnosis" and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Evaluation", section on 'Bronchoscopy'.)

Pulmonary vascular disease

Pulmonary cytolytic thrombi — Pulmonary cytolytic thrombi (PCT) are an unusual complication of allogeneic HCT; PCT is without known etiology, although it may be a manifestation of acute and chronic GVHD [101-104]. PCT is more common in children [60,102]. The clinical presentation is fever, cough and dyspnea; conventional chest radiographs are usually clear, but HRCT shows numerous peripheral tiny pulmonary nodules. Peripheral nodular lesions have a broad differential in allogeneic HCT recipients, including aspergillus infection, OP, metastatic malignancy, or idiopathic interstitial pneumonia [102]. As these processes require very different treatment, a definitive diagnosis is essential.

A surgical lung biopsy is usually necessary to make the diagnosis of PCT and is performed after the usual blood and BAL studies fail to identify an infection. The histopathology of PCT reveals basophilic cytolytic thrombi in the small to medium distal pulmonary vessels with entrapped monocytes [103]. Hemorrhagic infarcts are present, similar to those seen in invasive aspergillus infection, but stains and cultures for aspergillus are negative.

The optimal treatment for PCT is not known, although systemic glucocorticoid therapy has been associated with successful outcomes [102,105,106].

Pulmonary veno-occlusive disease — Pulmonary veno-occlusive disease (PVOD) occurs rarely after allogeneic HCT and may be a consequence of pretransplant chemotherapy for the underlying malignancy [107]. It generally occurs late in the course, after the first 100 days, and should be suspected in patients with dyspnea, reduced diffusing capacity (DLCO), mild restriction on pulmonary function tests, and no evidence of infection, particularly if there is evidence of pulmonary venous congestion on imaging studies and pulmonary arterial hypertension in the absence of left-sided heart disease on right heart catheterization.

Chest radiographs often reveal a pleural effusion and Kerley B lines may be noted. CT may reveal septal thickening, diffuse or mosaic ground glass opacities with a centrilobular distribution, multiple small nodules, or alveolar consolidation. CT pulmonary angiography is not helpful to diagnose PVOD, but may be performed to exclude pulmonary embolism. Doppler echocardiography shows pulmonary hypertension. Right-sided heart catheterization is necessary to document the combination of pulmonary hypertension and a normal pulmonary artery occlusion pressure. Occult alveolar hemorrhage may be found on BAL [108]. A presumptive diagnosis of PVOD is based on an integrated assessment of these findings; however, lung biopsy is required for definitive confirmation of the diagnosis.

The diagnosis and treatment of PVOD are discussed separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults" and "Treatment and prognosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

Other pulmonary vascular disease

Pulmonary hypertension (group 5: unidentified mechanism) has been noted in some patients with primary myelofibrosis who have not undergone HCT, as described separately. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Signs and symptoms' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

Dasatinib, a tyrosine kinase inhibitor used in the treatment of certain leukemias, is associated with pulmonary arterial hypertension that is at least partially reversible with drug discontinuation. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Dasatinib'.)

Drug toxicity and radiation pneumonitis — Allogeneic HCT recipients are at risk for lung toxicity due to the chemotherapeutic agents (eg, busulfan, cyclophosphamide, carmustine, sirolimus) and radiation therapy used for preparative conditioning, or for treatment of the underlying disease prior to HCT. (See "Busulfan-induced pulmonary injury" and "Cyclophosphamide pulmonary toxicity" and "Nitrosourea-induced pulmonary injury" and "Methotrexate-induced lung injury" and "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Respiratory system' and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents" and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)

Acute radiation pneumonitis usually develops 4 to 12 weeks after irradiation, whereas symptoms of late or fibrotic radiation pneumonitis develop after 6 to 12 months. (See "Radiation-induced lung injury".)

Both drug toxicity and radiation pneumonitis usually present with dyspnea and a nonproductive cough; fever may also be present. Chest radiographs can show patchy or diffuse opacities with ground glass or consolidative attenuation. The evaluation and treatment of cytotoxic antineoplastic agent and irradiation-induced lung injury are discussed separately. (See "Cyclophosphamide pulmonary toxicity" and "Busulfan-induced pulmonary injury" and "Methotrexate-induced lung injury" and "Radiation-induced lung injury".)

Airflow obstruction and bronchiolitis obliterans — Airflow obstruction developing after allogeneic HCT may be a consequence of HCT or may be due to bronchiolitis obliterans (BO). BO is manifest pathologically by development of small airways inflammation and narrowing due to fibrous scar. These changes are associated with the clinical finding of airflow limitation. The term bronchiolitis obliterans syndrome (BOS) is used when a patient has airflow limitation in the absence of other etiologies, but histopathology to document BO is not available. (See "Overview of pulmonary function testing in adults".)

Mild airflow limitation – Mild decrements in lung function are frequent following HCT, but are rarely symptomatic and chest radiographs are usually normal [109-111]. As an example, one study of 52 patients who received allogeneic or autologous bone marrow transplants during childhood found that spirometry, lung volume, and diffusing capacity measurements were within normal limits in only 62 percent [112]. However, none reported chronic respiratory symptoms. In a second study, airflow obstruction was present in 26 percent of patients after allogeneic HCT [109]. Risk factors for the development of airflow obstruction included older age, a history of acute or chronic GVHD, and respiratory viral infections in the early post-transplant period. The pathophysiology of this mild airways obstruction is not well understood, but does not appear to be related to airway hyperresponsiveness [113-115].

Bronchiolitis obliterans risk factors – Moderate-to-severe airflow obstruction is usually a manifestation of bronchiolitis obliterans, which is thought to be similar to BOS that is a manifestation of chronic rejection in lung transplant recipients (picture 1A-B) [116,117]. The cause of bronchiolitis obliterans after HCT is unknown, although risk factors such as chronic GVHD, ABO blood group incompatibility, use of peripheral blood stem cells, and certain viral infections have been identified [118-120].

Clinical presentation – Chronic GVHD is a late (>100 days) complication of allogeneic HCT. Initially, patients with bronchiolitis obliterans often have a normal lung examination and a clear chest radiograph. As the disease progresses, the chest CT may show bronchiectasis and a mosaic pattern of ground glass opacities [121]. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Diagnosis'.)

Diagnosis – BOS is suspected clinically when new airflow obstruction is found in the absence of infection (especially viral infection) and when the exam and high resolution CT chest with expiratory images are both suggestive of bronchiolitis. Care must be taken to exclude the infectious causes of bronchiolitis.

Initial treatment – Treatment of BOS following HCT is based on clinical experience and observational data. Some experts (including us) initiate treatment with high-dose inhaled glucocorticoids (eg, budesonide ≥720 mcg/day, fluticasone propionate ≥440 mcg/day) at the onset of mild airflow limitation (forced expiratory volume in one second [FEV1] ≥70 percent predicted, but <80 percent) and administer systemic immunosuppressive therapy as indicated for extrapulmonary manifestations of GVHD (table 3) [122,123].

An inhaled long-acting beta-agonist (LABA) may be used in combination, particularly if the patient is symptomatic [123-125]. The inhaled glucocorticoid is continued until airflow obstruction worsens or until six months after systemic immunosuppressive therapy for GVHD has been successfully discontinued.

Continued symptoms despite inhaled glucocorticoids – Many experts will expand the regimen to “FAM” therapy (ie, inhaled fluticasone 440 mcg twice daily, azithromycin 250 mg three times weekly, and montelukast 10 mg daily) for those patients who continue to have FEV1 decline and symptoms on inhaled glucocorticoids/LABA. This is based only upon small studies that demonstrate low risk and some evidence of FEV1 stability [126,127].

Progressive worsening of airflow limitation – If airflow limitation progresses (FEV1 <70 percent predicted) with or without significant air trapping on HRCT, infection is carefully excluded (see 'Pulmonary infections' above), and systemic glucocorticoids are initiated or increased to the equivalent of prednisone 1 mg/kg per day (table 3). For patients with worsening airflow limitation and requiring systemic glucocorticoids, additional agents may include azithromycin (250 mg) three times weekly and montelukast 10 mg/day, although supportive evidence is limited [126]. The dose of prednisone is tapered within two weeks of objective improvement in lung function with further tapering at two week intervals as tolerated.

Refractory bronchiolitis obliterans – Some patients with refractory BOS due to chronic GVHD respond to glucocorticoids and increased immune suppression, but often BOS is irreversible. Patients with refractory disease respond poorly to treatment and may progress to hypercapnia and respiratory failure [116,117,128-130]. In two small case series of patients with refractory disease, lung transplantation was successful [131,132]. In one series, 13 patients underwent lung transplantation and 11 survived (median follow-up 4.2 years), although 4 subsequently developed BOS in the lung allograft. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)

Prevention – According to a safety alert from the US Food and Drug Administration, azithromycin should not be used for prophylaxis against BOS after HCT pending further review [133]. This warning is based on a multicenter, randomized trial in which 480 patients were assigned to receive azithromycin 250 mg or placebo, three times per week, starting at the time of the conditioning regimen [134]. The trial was stopped early because of increased hematologic relapse in the azithromycin group. In addition, the azithromycin group experienced a decrease in airflow decline-free survival. This is in contrast to the beneficial effect of prophylactic azithromycin in improving BOS-free survival after lung transplantation.

SUMMARY AND RECOMMENDATIONS

Several aspects of allogeneic hematopoietic cell transplantation (HCT) contribute to the development of pulmonary disease, including previous treatment of the underlying disease, the pretransplant conditioning regimen, engraftment of donor cells, graft-versus-host disease (GVHD), and ongoing immunosuppression. The spectrum of pulmonary complications of allogeneic HCT varies depending on the timing after transplant and includes a broad spectrum of infectious, inflammatory, and neoplastic disorders (table 1 and table 2). (See 'Pre-engraftment period' above.)

Engraftment after HCT is defined as the attainment of an absolute neutrophil count (ANC) of 1000/microL, or three consecutive days with a count greater than 500/microL. Time to engraftment is variable, but on average is approximately 30 days from transplant. (See 'Engraftment' above.)

In the pre-engraftment period from HCT up to engraftment (eg, about 0 to 30 days post HCT), the differential diagnosis of pulmonary complications includes infection, pulmonary edema due to cardiac and noncardiac causes such as sepsis syndrome or aspiration, and the engraftment syndrome (table 1). Symptoms and signs are nonspecific and include fever, dyspnea, cough, and hypoxemia. (See 'Pre-engraftment period' above.)

The engraftment syndrome, an uncommon complication of allogeneic HCT, presents as a noncardiogenic pulmonary edema that may be associated with fever, an erythematous maculopapular rash, weight gain, hypoxemia, and diffuse pulmonary opacities. (See 'Engraftment syndrome' above.)

The spectrum of pulmonary complications changes after engraftment (>30 days after HCT, approximately). Infections continue to be a significant cause of morbidity and mortality, although the specific organisms differ (figure 1). Noncardiogenic and cardiogenic pulmonary edema are more common pre-engraftment, but also occur post-engraftment. The idiopathic pneumonia syndrome (IPS), diffuse alveolar hemorrhage, and pulmonary alveolar proteinosis are infrequent but can cause substantial pulmonary morbidity (table 2). (See 'Post hematopoietic cell engraftment' above.)

IPS is a form of noninfectious widespread alveolar injury that occurs up to four months after HCT. The main treatment for IPS is supportive care; empiric antibiotics are typically administered while awaiting microbiologic study results. For patients with more severe respiratory impairment, we suggest addition of high dose glucocorticoids (1 mg/kg or more), although benefit has not been clearly demonstrated (Grade 2C). (See 'Treatment' above.)

For HCT recipients who have received cardiotoxic medications as therapy for their underlying disease, cardiac dysfunction can be a cause of dyspnea and diffuse radiographic opacities. Cardiac dysfunction may be suspected in the absence of fever, chills, or night sweats, but it can present concomitantly with infection. The evaluation typically includes measurement of brain natriuretic peptide (BNP) and echocardiography. (See 'Pulmonary edema' above.)

The evaluation of pulmonary complications of allogeneic HCT is discussed separately. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Evaluation".)

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Topic 4339 Version 41.0

References

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